Project I (human infant) focuses on brain-behavior effects depending on the timing of iron deficiency (ID) and iron repletion in human infants. Iron deficiency (ID) is the world's most common single nutrient disorder, differentially affecting pregnant women and infants everywhere. Project I promises to be the first systematic investigation of brain and behavior effects of prenatal dietary iron deficiency in human infants (Aim 1). The design will support comparisons of brain/behavior effects depending on the timing and duration of ID (Aim 2). The study will assess reversibility of effects, depending on timing of ID and its treatment (Aim 3), and examine maternal vs. fetal iron regulatory mechanisms in placenta and white blood cells (Aim 4). State-ofthe- art neurophysiologic and behavioral measures will test specific hypotheses regarding effects of ID on sensory, motor, cognitive, affective-social and regulatory functions related to impaired myelination of sensory/motor systems and altered structure, neurotransmitter function and neurometabolism in targeted brain regions (basal ganglia and hippocampus). The study will be conducted in China, a rapidly developing country where ID often occurs among pregnant women and infants in the absence of generalized undernutrition. Cord blood hemoglobin (Hb) andferritin concentrations will be measured in 1122 rural fullterm infants, with iron status determined again at 9 and 18 mo. Brain-behavior assessments in the perinatal period will involve 359 infants ("newborn cohort"): 59 with low Hb ("low birth iron" group) will receive iron;200 with marginal Hb or low cord ferritin ("marginal birth iron" group) will be randomly assigned at 6 wk, 50 to iron therapy and 150 to placebo;and 100 with normal cord Hb and ferritin levels ("normal birth iron" group) will receive placebo. The remaining 763 infants with cord blood testing will form the "blood screen cohort." At 9 and 18 mo, the newborn cohort will be reassessed, along with IDA infants from the blood screen cohort - about 58 at 9 mo ("early postnatal IDA") and 48 at 18 mo ("late postnatal IDA"). Approximately 39 marginalbirth- iron placebo-treated infants in the newborn cohort may also have IDA at 9 mo ("combined ID"). IDA infants will be treated with iron. Project I is tightly linked conceptually and methodologically with monkey and rodent projects in PPG2 and builds directly on findings in all projects in PPG1. Differential effects and/or reversibility depending on timing of ID or treatment could inform health policy and practice worldwide. However, the effects of prenatal iron deficiency have received very little study in human infants due in large part to previous thinking, no longer accepted, that the infant was protected. Up to 75% of pregnant women worldwide are anemic, with about half due to ID. An estimated 20-25% of 6- to 24-mo-old infants have IDA, and more have ID without anemia. Thus, the public health implications of study findings, especially in combination with Project II-IV animal models, could be profound.